We have previously reported the discovery of a series of rhodanine-based inhibitors of the PIM family of serine/threonine kinases. Here we described the optimisation of those compounds to improve their physicochemical and ADME properties as well as reducing their off-targets activities against other kinases. Through molecular modeling and systematic structure activity relationship (SAR) studies, advanced molecules with high inhibitory potency, reduced off-target activity and minimal efflux were identified as new pan-PIM inhibitors. One example of an early lead, OX01401, was found to inhibit PIMs with nanomolar potency (15 nM for PIM1), inhibit proliferation of two PIM-expressing leukaemic cancer cell lines, MV4-11 and K562, and to reduce intracellular phosphorylation of a PIM substrate in a concentration dependent manner.

我们之前已经报道了PIM丝氨酸/苏氨酸激酶家族中基于罗丹宁的一系列抑制剂的发现。在这里，我们描述了优化这些化合物以改善其理化和ADME特性，以及降低其针对其他激酶的脱靶活性的优化方法。通过分子建模和系统结构活性关系（SAR）研究，具有高抑制力，降低脱靶活性和最小外排的先进分子被确定为新型pan-PIM抑制剂。发现了一个早期铅OX01401的实例可抑制具有纳摩尔效价的PIM（PIM1为15 nM），抑制两种表达PIM的白血病癌细胞系MV4-11和K562的增殖，并减少PIM的细胞内磷酸化底物以浓度依赖的方式。